Natural Products: The Big Picture
Bacteria, fungi and plants produce incredible molecules that humans use as antibiotics, anticancer agents, immunosuppressants, and more. Our lab is interested in learning how these organisms build such structurally complex and pharmacologically relevant molecules. We hope to apply this information to build new and environmentally sustainable routes to new antibiotics and other important chemicals.
Our research centers around two main threads of inquiry:
- How does nature drive chemical innovation? How can we use evolutionary history as a roadmap for future engineering efforts?
- How do proteins within an organism communicate to build complicated molecules? Can we use this information to mix-and match-proteins from different biosynthetic pathways to synthesize novel molecules?
How does nature drive chemical innovation? How can we use evolutionary history as a roadmap for future engineering efforts?
Biosynthetic gene clusters (BGCs) are physically grouped collections of genes which encode the team of proteins that work together (termed ‘synthase’) during the biosynthesis of many natural products. With modern technology, researchers have developed a myriad of methods to identify and study these BGCs from large sets of genetic data. Hence, evolutionary analysis of characterized gene clusters can lead to the discovery of novel BGCs, which can be mined for new molecules and enzymes.
In 2015, in collaboration with Dr. Maureen Hillenmeyer (HexagonBio), we unveiled key mechanisms that nature uses to drive type II polyketide chemical diversity, identifying fertile ground for the discovery of novel antibiotics. We can use this history as a roadmap for rational engineering efforts and to mine unexplored regions of the phylogenetic tree, uncovering molecules and enzymes of novel structure and function along the way.
Now, we seek to update this evolutionary analysis with recent genetic data. These efforts will guide the future study of specific polyketide synthase pathways and, in turn, unique iterations of their enzymes.
How do proteins communicate to build complicated molecules? And can we use this information to mix-and-match proteins from different biosynthetic pathways to synthesize novel molecules?
We are interested in understanding how microorganisms use enzyme assemblies to make important pharmaceutical agents. We develop innovative approaches to study transient protein-protein and protein-substrate interactions, including site-specific vibrational spectroscopy with Casey Londergan (Haverford Chemistry) and analytical ultracentrifugation with Robert Fairman (Haverford Biology). Using these and other traditional biochemical approaches such as NMR and x-ray crystallography, we characterize the molecular interactions of the carrier proteins that are central to functioning natural product synthases. Current focuses also include molecular dynamic simulations and biochemical binding assays.
CURE: Original Research in the Classroom
Integrating Teaching and Research
To encourage a relevant and exciting learning environment, I seek to reflect the interdisciplinary nature of modern science in my introductory courses, and incorporate original research into the classroom in my upper-level classes.
Incorporating Original Research in the Classroom
What could be a better way to introduce students to real chemistry than to turn the classroom into an original research experience? Through incorporating projects such as “The Fungal Challenge” in upper-level seminar classes, and tackling cutting edge research questions in junior-level Superlab courses, our students develop their skills at the chemistry-biology interface while making meaningful contributions to the natural products community.
Designing Convergent Chemistry Curricula
Scientific convergence is a common theme in modern research, yet undergraduate chemistry is commonly taught as an isolated discipline. We strive to increase scientific convergence in introductory chemistry courses. In collaboration with Dr. Joshua Kritzer, Dr. Krishna Kumar, and Dr. Nicole Sampson, we have created a web-based resource to compile details of curricular changes in college-level general chemistry and organic chemistry sequences.
At http://sites.tufts.edu/ConvergentChemistry, you can view curricular innovations from a large variety of colleges and universities. We encourage new submissions, and the site will be continuously curated with additions and updates! You can also read our commentary “Designing covergent chemistry curricula” in Nature Chemical Biology.